EP1798250B1 - Zur Bindung an Metallschichten geeignete Moleküle zur kovalenten Immobilisierung von Biomolekülen - Google Patents

Zur Bindung an Metallschichten geeignete Moleküle zur kovalenten Immobilisierung von Biomolekülen Download PDF

Info

Publication number
EP1798250B1
EP1798250B1 EP06026155A EP06026155A EP1798250B1 EP 1798250 B1 EP1798250 B1 EP 1798250B1 EP 06026155 A EP06026155 A EP 06026155A EP 06026155 A EP06026155 A EP 06026155A EP 1798250 B1 EP1798250 B1 EP 1798250B1
Authority
EP
European Patent Office
Prior art keywords
group
ethoxy
metal layer
integer
species
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP06026155A
Other languages
English (en)
French (fr)
Other versions
EP1798250A2 (de
EP1798250A3 (de
Inventor
Filip Frederix
Kristin Bonroy
Karolien Jans
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Interuniversitair Microelektronica Centrum vzw IMEC
Original Assignee
Interuniversitair Microelektronica Centrum vzw IMEC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Interuniversitair Microelektronica Centrum vzw IMEC filed Critical Interuniversitair Microelektronica Centrum vzw IMEC
Publication of EP1798250A2 publication Critical patent/EP1798250A2/de
Publication of EP1798250A3 publication Critical patent/EP1798250A3/de
Application granted granted Critical
Publication of EP1798250B1 publication Critical patent/EP1798250B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
    • B05D1/185—Processes for applying liquids or other fluent materials performed by dipping applying monomolecular layers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2610/00—Assays involving self-assembled monolayers [SAMs]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00—Metal working
    • Y10T29/49—Method of mechanical manufacture
    • Y10T29/49002—Electrical device making
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/24—Structurally defined web or sheet [e.g., overall dimension, etc.]

Definitions

  • the invention relates to the field of sensors, particularly biosensors for detecting an analyte in a sample, especially sensors comprising a metal layer substrate and one or more organic molecules bound to said substrate.
  • the present invention relates as well to the manufacture of such sensors, and organic molecules suitable for use in such sensors.
  • biosensors and biochips capable of characterizing and quantifying (bio)molecules.
  • biosensors and biochips capable of characterizing and quantifying (bio)molecules.
  • affinity-based biosensors or immunosensors These sensors are expected to revolutionize in areas like diagnostics, food processing, antiterrorism, environmental monitoring and public health where rapid detection combined to high sensitivity are important.
  • the immobilization reaction should have several characteristics. First, the reaction should occur rapidly and therefore allow the use of low concentrations of reagents for immobilization. Second, the chemistry should require little, if any, post-synthetic modifications of ligands before immobilization to maximize the number of compounds that can be generated by solution or by solid-phase synthesis and minimize the cost of these reagents. Third, the immobilization process should occur selectively in the presence of common functional groups, including amines, thiols, carboxylic acids, and alcohols, to ensure that ligands are immobilized in a preferable oriented and homogeneous manner. Finally, the reaction should have well-behaved kinetics and be easily monitored with conventional spectroscopic methods to control the density of ligands on the chip.
  • a method for immobilizing proteins on mixed self-assembled monolayers of alkanethiols is also known in the art.
  • This method needs an activation step comprising forming a N-hydroxysuccinimidyl (NHS) ester from the carboxylic acid groups of the self-assembled monolayer and then coupling this ester to a free amino group of the protein.
  • NHS N-hydroxysuccinimidyl
  • a self-assembling monolayer having free carboxylic acid groups is formed onto a gold surface.
  • the surface carboxylic acid groups are activated to form the NHS ester, followed by displacement of the NHS ester with an amino group of the protein to form an amido function. Since several steps have to be performed after deposition of the self-assembling monolayer onto the substrate, the yield reduces after each step, resulting in a low final yield of the immobilization degree.
  • Thiolate or disulfide self-assembled monolayers with aldehyde or epoxy end groups, which can be directly coupled to functional groups on biomolecules or bioreceptors are also known in the art.
  • these self-assembled monolayers do not incorporate poly(ethylene oxide) groups allowing a better sensitivity and specificity of the final biosensor interface.
  • Self-assembled monolayers with pre-activated groups e.g. dithiobis(succinimidylundecanoate), dithio-bis(succinimidylpropionate) and dithiobis(succinimidylhexadecanoate) are already known in the art and can incorporate poly(ethylene oxide) groups.
  • dithiobis(succinimidylundecanoate), dithio-bis(succinimidylpropionate) and dithiobis(succinimidylhexadecanoate) are already known in the art and can incorporate poly(ethylene oxide) groups.
  • N-hydroxysuccinimidyl group is very sensitive to hydrolysis, which makes it difficult to store these activated samples before use.
  • Self-assembled monolayers incorporating poly(ethylene oxide) groups and a preactivated maleimidyl group are also known in the art.
  • a maleimide reacts preferentially with free thiol groups, which are not always readily available in proteins such as antibodies.
  • antibodies can be reduced to generate free thiol groups but this additional step is difficult to perform when forming biochips and often decreases the antibody affinity.
  • Affinity biosensor transducers are defined as systems containing at least one biological element able to recognize an analyte. This element is called the biological recognition layer and consists of a probe molecule, covalently bound to a linking layer, which makes the connection with the transducer.
  • the substrate can be a deposit of a metal film on any convenient support or any other solid surface able to selectively bind monolayers.
  • Preferred metals include gold, silver, Ga-As alloys, palladium, platinum, copper, and the like.
  • Silanes and alkyl phosphate monolayers can also be used on oxide material substrates like SiO 2 , Nb 2 O 5 , TiO 2 , ZrO 2 , Al 2 O 3 , and Ta 2 O 5 .
  • a biosensor must respond to major qualities like stability, specificity, selectivity, and reproducibility. For all those reasons, only few affinity biosensors are commercially available. The major challenge being the realization of new specific and selective self-assembled monolayers and the receptors. An analyte must be detectable in an excess of other proteins.
  • the most common receptors are antibodies and specific binding proteins which have a reversible specific binding affinity for an analyte. Chemical modifications of the surface moieties may create new surface functionalities, such as, for example, amine-terminated functional groups appropriate for particular diagnostic or therapeutic operations.
  • One aim of the invention is to provide new organic molecules suitable for forming a self-assembling monolayer onto a surface, in particular a metal surface.
  • One advantage of the present invention is that it can solve one or more of the problems identified herein above.
  • the present invention can provide mixed self-assembled monolayers of thiols or disulfide molecules incorporating poly(ethylene oxide) groups and two functional groups, preferably wherein one functional group is pre-activated and can be directly and covalently coupled to the amino groups of a bioreceptor while the other functional group provides resistance to non-specific adsorption.
  • the present invention can also provide organic molecules that can form self-assembling monolayers suitable for making high selectivity, high stability and/or high reproducibility sensor substrates linked to a recognition molecule. In addition these organic molecules can decrease non-specific binding and allow binding of a receptor molecule onto the self-assembling monolayer in one single step.
  • this invention relates to an organic molecule having the structural formula X 1 -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n -R 1 -S-X 2 , wherein :
  • X 1 represents a group which can directly react with a biomolecule, i.e. without prior activation of either the organic molecule of this invention or the biomolecule to be immobilised.
  • the biomolecule has at least one primary aminogroup, which can react with the X 1 group.
  • the amino group of a lysine amino acid of a protein/peptide or the amino group at the end of a DNA or RNA strand or oligo nucleic acid chain can react with the molecule X 1 -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n -R 1 -S-X 2 at the X 1 side of the molecule.
  • the group -([CH 2 ] t -CH 2 -O) n - in X 1 -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n -R 1 -S-X 2 and in R 2 -(O-CH 2 -[CH 2 ] t ) n -O-(CH 2 ) c -X 1 ' is preferably selected in such a way that non-specific adsorption of a biomolecules to the organic molecule of this invention is substantially avoided.
  • X 1 and X 1 ' each independently include a chemical group compatible with monolayer formation and which needs no in situ activation prior to reaction with the biological moiety.
  • this invention relates to a device for immobilizing at least one biomolecule through a covalent bond, said device comprising:
  • the device further comprises a second species, the second species being bound onto the metal layer and including a compound having the chemical formula: Y 1 -([CH 2 ] t -CH 2 -O) n -R 3 -S-M wherein:
  • the second species is preferably selected such that non-specific adsorption of biomolecules is substantially avoided.
  • this invention provides a process for preparing a device according to the second aspect of the present invention. This process comprises the steps of:
  • the present invention relates to a sensor for the detection of an analyte in a sample fluid, the sensor comprising:
  • the present invention relates to a method for manufacturing a sensor according to the fifth aspect of the present invention, wherein the method comprises the steps of:
  • the at least one biomolecule has at least one primary amino group.
  • the device and/or said at least one biomolecule is not chemically activated prior to contacting.
  • the term "self-assembling" relates the association of molecules without guidance or management from an outside source. It results in a layer, usually a monolayer of those molecules on a surface.
  • metal layer relates to a layer made from one or more metals or metal alloys, having a thickness ranging from 1 nm to 10 mm (but not limited hereto) and which can be either self supported or supported by a substrate. If the layer is self-supported, it can be named " substrate " as well.
  • hydrocarbyl group relates to a saturated or ethylenically unsaturated, cyclic or non-cyclic chain selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl cycloalkyl-alkyl, cycloalkenyl-alkyl and cycloalkyl-alkenyl; when non-cyclic, this chain can be linear or branched.
  • halide relates to a compound comprising a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide.
  • an organic molecule is provided with the structural formula: X 1 -PEO1-R 1 -S-X 2 wherein:
  • R 1 and R 2 independently include an alkyl chain -(CH 2 ) n , n being an integer between 3 and 30, for instance between 3 and 25, preferably between 3 and 20, e.g. between 5 and 20, or between 8 and 16.
  • n is an integer.
  • n is higher than 4, higher than 6, higher than 8, higher than 10, higher than 11, higher than 12, higher than 13, higher than 15 or higher than 20.
  • n is an integer between 8 and 16, between 10 and 16.
  • R 1 and R 2 are each independently a saturated or ethylenically unsaturated hydrocarbyl group with 3 to 30 carbon atoms selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenyl, cycloalkenylalkyl and cycloalkylalkenyl, said group optionally comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur in the main chain, and said group optionally comprising one or more oxo substituents.
  • PEO1 and PE02 independently include a -(O-CH 2 -[CH 2 ] t ) n -O- group, n being an integer between 3 and to 15,000, preferably between 3 and 1250. PEO1 and PE02 are preferably selected such that non-specific adsorption of chemical molecules is avoided. PEO1 and PE02 independently include (O-CH 2 -[CH 2 ] t ) n -O-such as e.g.
  • n being an integer between 3 and 15,000, preferably between 3 and to 1250, between 3 and 1000, between 3 and 500, between 3 and 100, between 3 and 50, between 3 and 30, between 3 and 20, between 3 and 15, between 3 and 10, between 3 and 8, or between 2 and 8.
  • n is an integer between 1 and 30, between 1 and 20, between 1 and 15, between 1 and 10, between 1 and 8, or between 1 and 6.
  • t is an integer between 1 and 10, preferably 1 or 2.
  • PEO1 is represented by the structural formula -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n and PE02 is independently from PEO1 represented by the structural formula -(O-CH 2 -[CH 2 ] t ) n -O-(CH 2 ) c -, n being an integer and c being an integer.
  • the groups -(O-CH 2 -[CH 2]t ) n are intended for avoiding non-specific adsorption.
  • the variable " n " is preferably between 1 to 10, or between 1 to 8.
  • the variable " c" is an integer between 0 and 3, preferably between 1 and 3.
  • c can be 1, 2, or 3.
  • the variable " t " is 1 or 2.
  • X 1 is a chemical group suitable for binding biological moieties (e.g. a biomolecule) onto a monolayer. More specifically, X 1 is a highly reactive functional moiety compatible with monolayer formation and which needs no in situ activation prior to reaction with the biological moiety.
  • the biological moieties that are covalently bound or adsorbed onto the monolayer can be, but are not limited to, nucleic acid strands (DNA, PNA, RNA), proteins, hormones, antibiotics, antibodies, chemically or enzymatically modified antibodies, VHH fragments of lama antibodies, synthetic receptors, single chain Fv's, antigens, enzymes, drugs, drugs of abuse. In general, these biological moieties will serve as a biological sensing element and will be part of a sensor.
  • the resulting sensor will be suitable for determining the presence of a compound, such as a target molecule, which interacts with the biological sensing element.
  • a compound such as a target molecule
  • the target molecule could be, but is not limited to, complementary nucleic acid strands (DNA, PNA, RNA), proteins, hormones, antibiotics, antibodies, antigens, enzymes, drugs, drugs of abuse or molecules such as specific molecules present in for example gases and liquids.
  • X 1 includes preferably a chemical group selected from the group consisting of fluorophenyl, fluorobenzoyl, fluorophenoxycarbonyl, nitrophenoxycarbonyl, oxirane, aziridine, C 2-12 alkenyl, imino-ether, dichlorotriazinyl, sulfonyl halide, alkoxycarbonyl, isothiocyanato, isocyanato, carbonyl halide, haloalkylcarbonyl, carboxylic acid anhydride, diazonium carbonyl, N-(2-oxotetrahydro-3-thienyl) amido and N-carboxy-thiazolidine-2-thione.
  • X 1 is a chemical group for binding biological moieties to the molecule as recited in the first aspect of this invention.
  • the chemical group X 1 is used for immobilization of a molecule, e.g. a recognition molecule.
  • the recognition molecule can be e.g. a biomolecule.
  • the recognition molecules can chemically interact (e.g. bind) to the group X 1 and in particular the NH 2 group of a recognition molecule can bind to the group X 1 or can react with the group X 1 to bind to molecule X 1 -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n -R 1 -S-X 2 .
  • X 1 is a highly reactive functional moiety compatible with monolayer formation and which needs no in situ activation prior to reaction with the biological moiety.
  • the biological moieties that can covalently be bound or adsorbed to the chemical molecule as recited in the first aspect of this invention can be, but are not limited to, nucleic acid strands (DNA, PNA, RNA), proteins, hormones, antibiotics, antibodies, chemically or enzymatically modified antibodies, VHH fragments of lama antibodies, synthetic receptors, single chain Fv's, antigens, enzymes, drugs, drugs of abuse. In general, these biological moieties will serve as a biological recognition molecule.
  • the molecule having the structural formula X 1 -PEO1-R 1 -S-X 2 corresponds to the structural formula X 1 -(CH 2 ) c -PEO1-R 1 -S-X 2 .
  • the structural formula X 1 -PEO1-R 1 -S-X 2 corresponds to the structural formula X 1 -(CH 2 ) c -O-([CH 2 ] t -CH 2 -O) n -R 1 -S-X 2 wherein
  • the functional group -S-S- or H-S- is able to adhere (i.e. chemi-sorb) to a surface such as a metal layer and can chemically interact (e.g. bind) with said metal layer.
  • a covalent bond S-M with S being a sulfur atom and M being the metal, can be formed.
  • S-M with S being a sulfur atom and M being the metal, can be formed.
  • the interaction between the sulfur atom and the substrate is well known to people skilled in the art.
  • a device suitable for the fabrication of a sensor in disclosed.
  • the device comprises:
  • a device for immobilizing at least one biomolecule through a covalent bond comprising:
  • the device as recited in the second aspect of this invention further comprises a second species, said second species being bound to the metal surface (i.e. the metal layer), the second species being obtained by contacting the metal layer with a compound of the structural formula: Y 1 -R 3 -S-Y 2 wherein:
  • R 3 and R 4 can have the same chemical composition such that a symmetrical molecule is formed.
  • R 3 and R 4 are independently a spacer of m carbon atoms, m being an integer between 3 and 30, between 3 and 25, between 3 and 20, between 5 and 20, or between 8 and 16.
  • the total number of carbon atoms m is preferably higher than 3, higher than 6, higher than 8, or higher than 10.
  • R 3 and R 4 may include q heteroatoms wherein (m+q) is an integer preferably higher than 6.
  • R 3 and R 4 are independently selected from the group consisting of alkyl chains (CH 2 ) m with m being an integer higher than 6 and alkyl chains including q heteroatoms, q being an integer such that (m + q) is higher than 6.
  • R 3 and R 4 are independently from each other a spacer including two parts, a first part for obtaining a stable ordered monolayer and a second part for avoiding non-specific adsorption.
  • R 3 and R 4 are independently from each other (CH 2 ) e -(CH 2 -CH 2 -O) f -(CH 2 ) g , e being an integer, f being an integer and g being an integer.
  • the alkyl chain is intended to achieve a stable ordered and reproducible system while the polyethylene oxide groups are intended for avoiding non-specific adsorption.
  • the variable " e " is preferably an integer from 1 to 20, from 5 to 20, from 5 to 15, or from 5 to 12, e.g. 6 or 11.
  • the variable " f " is preferably an integer from 1 to 10, from 1 to 8, or from 2 to 6, e.g. 3, 4 or 5.
  • the variable " g " is an integer preferably from 0 to 3, e.g. 1 or 2.
  • the device as recited in the second aspect of this invention further comprising one or more second species bound onto said metal layer, wherein each of said one or more second species is a molecule having a structural formula Y 1 -([CH 2 ] t -CH 2 -O) n -R 3 -S-M wherein:
  • the first species and the second species are selected such that a mixed self-assembled layer such as a mixed self-assembled monolayer is formed on the metal layer.
  • a mixed self-assembled monolayer results in better sensitivity of the recognition molecule towards the target molecule in the medium.
  • the molar ratio of the second species to the first species can be 1000:1, 500:1, 100:1, 80:1, 70:1, 60:1, 50:1, 20:1, 10:1, 5:1, 95:5, 90:10, 80:20, 70:30, or 60:40, and can be determined by spectroscopic techniques available to a person skilled in the art.
  • Non-specific adsorption is preferably avoided when the device is used as a sensor.
  • Non-specific adsorption herein refers to interaction between the recognition molecule immobilized at the surface and any species being present in a medium that preferably contains the target molecule. Such "any species " excludes the target molecule.
  • the first species has the structural formula as recited in any of the examples.
  • the substrate may comprise a metal layer comprising, but not limited hereto, gold, silver, mercury, aluminum, platinum, palladium, copper, cadmium, lead, iron, chromium, manganese, tungsten and alloys thereof.
  • the substrate can be the metal layer itself.
  • the substrate can also be a sensor, a biosensor, a DNA chip, a protein chip, a microarray, a microscope slide, a silicon wafer or a microelectronic surface.
  • the substrate can be a part of a transducer, which can be, but is not limited to, a Surface Plasmon Resonance sensor, a Surface Acoustic Wave sensor, a Quartz Crystal Microbalance, an amperometric sensor, a capacitive sensor, an Interdigitated Electrode or a ChemFET sensor.
  • the surface can also have magnetic properties such as a magnetic particle comprising a magnetic material such Fe 2 O 3 or Fe 3 O 4 , optionally coated with a coating layer, preferably a metal coating layer.
  • the first species forms a self-assembling monolayer onto the surface of the device.
  • Self-assembled monolayers are considered as a relative ordered assembly of molecules that spontaneously attach (or chemisorb) onto a surface.
  • Molecules are preferably oriented parallel or preferably under an angle with respect to the surface.
  • Each group being part of a self-assembling monolayer preferably includes a functional group for attaching to the surface and a functional group that binds to the recognition molecule.
  • the functional group being able to attach to the surface is a disulfide group -S-S- or a thiol group
  • the functional group being able to bind a recognition molecule is the group X 1 as defined herein above.
  • the functional group -S-S- or HS- is able to adhere (chemisorb) to a surface such as a metal and can chemically interact with the metal surface. Interaction between the sulfur atom and the substrate is well known to people skilled in the art.
  • the chemical group X 1 is used for surface immobilization of a recognition molecule.
  • the recognition molecules can be bound to this group and in particular, a NH 2 group (i.e. at least one primary amino group) of a recognition molecule can react with the first species, i.e. with the group X 1 present on this first species.
  • Figure 1 represents schematically a device according to an embodiment of the second aspect of the present invention.
  • This device comprises a metal layer (2) on which a first species (1) and a second species (3) are bound.
  • the first and the second species form a monolayer (4) on the metal layer (2).
  • this invention provides a process for preparing a device according to the second aspect of the present invention. This process comprises the steps of:
  • a treatment to remove any metal oxide layer present at the surface of the metal layer is performed according to any method well known by the person skilled in the art.
  • Figure 2 shows a cyclic voltammogram (CV) of a gold layer without a mono-layer of molecules on its surface (Blanc, light line), a CV of the same gold layer on which a mono-layer of molecules according to example 7 has been self-assembled (100% COpfp doted line) and a CV of the same gold layer on which a mono-layer of molecules according to example 8 has been self-assembled (100% COOpfp, dark line).
  • the signal of the current in CVs of the gold layers on which a mono-layer of molecules according to the present invention has been formed show a dramatic decrease when compared with the signal of the current recorded for the gold surface alone. This indicates a substantially complete coverage of the gold layer by the respective self-assembled mono-layers.
  • a process for preparing a device according to an embodiment of the second aspect of this invention comprising the steps of:
  • a treatment to remove any metal oxide layer present at the surface of the metal layer is performed according to any method well known by the person skilled in the art.
  • the present invention relates to a sensor for the detection of an analyte in a sample fluid comprising:
  • Figure 3 shows the surface plasmon resonance (SPR) signal obtained for various concentrations of a prostate specific antigen (PSA) put in presence of an anti-PSA antibody immobilized on a gold surface via covalent bonding with a monolayer of species obtained from example 8 of the present invention.
  • the binding signals are expressed in resonance units (RU).
  • Figure 4 shows comparative SPR data for the immobilization of anti-PSA antibody on [1] a self-assembled monolayer of the prior art activated via an activation step with a carbodiimide followed by a pentafluorophenol binding and [2] on a self-assembled monolayer according to example 8 of the present invention.
  • the binding signal is expressed in resonance units (RU) and this signal is clearly higher in the case of the exemplary embodiment of the present invention.
  • the present invention relates to a method for manufacturing a sensor according to the fifth aspect of the present invention, wherein the method comprises the steps of:
  • the at least one biomolecule has at least one primary amino group.
  • the device and/or said at least one biomolecule is not chemically activated prior to contacting.
  • Example 1 synthesis of 2- ⁇ 2-[2-(11-mercapto-undecyloxy)ethoxy]ethoxy ⁇ ethyl 2,3,4,5,6-pentafluorobenzoate and analogues derived from higher polyethylene glycols.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • a solution of the thioacetate in DMF was activated with dicyclohexyl-carbodiimide under an atmosphere of nitrogen by stirring at room temperature for about 12 hours and then pentafluorophenol was added.
  • the reaction mixture was stirred at room temperature and extracted with water.
  • the reaction mixture was concentrated by rotary evaporation at reduced pressure and purification by chromatography on silica gel.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • Example 4 synthesis of 1-chloro-3-(2-[2-(11-mercaptoundecyloxy)-ethoxy]ethoxy) propan-2-one and analogues derived from higher polyethylene glycols.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • Example 5 synthesis of 11-(2-(2-(2-(2-(oxiran-2-ylmethoxy)ethoxy)ethoxy)-ethoxy)undecane-1-thiol and analogues derived from higher polyethylene glycols.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • the resulting product was concentrated using rotary evaporation.
  • the olefin was deprotected in a mixture of (1/1) HCl and H 2 O under an atmosphere of nitrogen.
  • the reaction mixture was then concentrated by rotary evaporation at reduced pressure and extracted with dichloromethane and water.
  • the organic portion was dried over MgSO 4 and concentrated by rotary evaporation at reduced pressure.
  • the product was purified by chromatography on silica gel.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • Example 7 synthesis of 2- ⁇ 2-[2-(2- ⁇ 2-[2-(11-mercapto-undecyloxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ⁇ ethyl 2,3,4,5,6-pentafluoro-benzoate and analogues derived from higher polyethylene glycols.
  • the present molecule has been synthesized according to the following synthesis scheme in three steps:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 0.0058 mole of 2-[2-(2- ⁇ 2-[2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ethanol was dissolved in a sufficient amount of ethanol. 0.023 mole of thioacetic acid and 10 mg of 2,2'- azobis-isobutyronitrile (AIBN) were added and the solution was irradiated with UV light for 24 hours under an atmosphere of argon.
  • AIBN 2,2'- azobis-isobutyronitrile
  • the product was purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using ethyl acetate/methanol (95/5).
  • the product was obtained in 89% yield and was characterized by its proton nuclear magnetic resonance spectrum as follows: 1 H NMR (300MHz, CDCl 3 ): ⁇ 3.65 (20H, m), ⁇ 3.45 (2H, t), ⁇ 2.85 (2H, t), ⁇ 2.5 (1 H, s), ⁇ 2.30 (3H, s), and 1.65-1.23 (18H, m).
  • step 2 in a dry bottle having a magnetic stirrer and under argon atmosphere, 0.0052 mole of the product obtained in step 1 was dissolved in a sufficient amount of CH 2 Cl 2 . 0.00785 mole of triethylamine was added and the solution was stirred for 1 hour under an atmosphere of argon. 0.00785 mole of pentafluorobenzoyl chloride was then added and the solution was stirred for 24 hours under an atmosphere of argon. The product was purified by rotary evaporation at reduced pressure and by purification on a silica column using ethyl acetate/methanol (95/5).
  • 0.00248 mole of the product obtained in step 2 was dissolved in an excess amount of solution containing 1 M HCl and EtOH (1/1). The solution was stirred for 24 hours. The solution was then extracted with diethyl ether and H 2 O. The organic phase was dried on MgSO 4 . The product was then concentrated using rotary evaporation. Next, the product was purified on a silica column using ethyl acetate. The product was again concentrated using rotary evaporation. The product was obtained in 56% yield and was characterized by its proton and carbon nuclear magnetic resonance spectra as follows:
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2-[2-(2- ⁇ 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]-ethoxy ⁇ ethoxy)ethoxy]ethoxy ethanol.
  • type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • Example 8 Synthesis of 2- ⁇ 2-[2-(2- ⁇ 2-[2-(11-mercaptoyldisulfanylundecyloxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ⁇ acetic acid pentafluorophenyl ester and analogues derived from higher polyethylene glycols.
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 9.2 mmole of 2-[2-(2- ⁇ 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ -ethoxy)ethoxy]ethoxy ethanol and 13.8 mmole of sodium hydride were dissolved in 50 mL DMF. The solution was stirred for 30 minutes. 13.8 mmole of methyl bromo-acetate was added and the solution was stirred for 24 hours under an atmosphere of argon. The product was quenched with 25 mL of methanol. The solution was then extracted with diethyl ether and H 2 O. The organic phase was dried on MgSO 4 .
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1.2 mmole of the product obtained in step 2 was dissolved in a sufficient amount of methanol. 4.6 mmole of thioacetic acid and 10 mg of 2,2'-azobis-isobutyronitrile (AIBN) were added and the solution was irradiated with UV light for 24 hours under an atmosphere of argon.
  • the product was purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using ethyl acetate/methanol (95/5).
  • a third step in a dry bottle comprising a magnetic stirrer, 1 molar equivalent (0.2 g) of the product obtained in step 2 was dissolved in a solution containing methanol/ 1 M NaOH (3/1) (15 mL/ 5mL). The solution was stirred for 24 hours. HCl was added to acidify the solution. The solution was then extracted with CH 2 Cl 2 and H 2 O. The organic phase was dried on MgSO4.
  • a fourth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 9.5 10 -5 mole of the product obtained in step 3 and 1.14 10 -4 mole pentafluorophenol (PFP) was dissolved in dry ethyl acetate (100mL). The solution was stirred and cooled down to 0°C. 1.14 10 -4 mole dicyclohexyl-carbodiimide (DCC) was added and the solution was stirred for 30 minutes. Next, the solution was stirred for 3 days at room temperature. The product was concentrated by rotary evaporation at reduced pressure. The product was obtained in 84% yield and was characterized as follows:
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol derivative is used instead of 2-[2-(2- ⁇ 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ethanol.
  • type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethyleneglycol involved.
  • Example 9 Synthesis of 2-(2-(2-(2-(11-2-(allyloxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy undec-6-ene-1-thiol and analogues derived from higher polyethylene glycols.
  • a first step in a dry bottle comprising a magnetic stirrer, a ball cooler and under argon atmosphere, 1 molar equivalent of 5,10-undecadien-1-ol is dissolved in dry dichloromethane.
  • the bottle is cooled in a mixture of acetone and dry CO 2 (-23°C).
  • 1 molar equivalent of triphenylphosphine and 1 molar equivalent of N-bromosuccinimide is added.
  • the reaction mixture is stirred for 1 hour at a temperature of -23°C and afterwards for 1 ⁇ 2 h at room temperature.
  • the solution is extracted with a solution of natriumcarbonate.
  • the organic phase is dried on MgSO 4 .
  • the product is then concentrated using rotary evaporation.
  • the product is extracted with hexane under reflux.
  • the product is filtered via vacuum filtration on alumina (5 cm in height and 3 cm diameter) and washed with hexane.
  • the product is again concentrated
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 2 molar equivalents of triethylene glycol is dissolved in a mixture of THF/DMF. 1 molar equivalent of sodium hydride is added and the solution is stirred for 1 hour under an atmosphere of argon. 1 molar equivalent of the product obtained in step 1 is added, and the reaction mixture is stirred for 3 days under an atmosphere of argon.
  • the product is quenched with MeOH. THF and DMF are removed by rotary evaporation at reduced pressure.
  • the product is extracted with dichloromethane and H 2 O.
  • the organic phase is dried on MgSO 4 .
  • the product is then concentrated using rotary evaporation.
  • the product is purified on a silica column using a suitable mixture of organic solvents, known by persons skilled in the art.
  • the product is again concentrated using rotary evaporation.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-Azobis(lsobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • a fourth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 3, is dissolved in CH 2 Cl 2 . 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of allyl bromide is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known by persons skilled in the art.
  • a fifth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 4 is dissolved in a solution containing 1 M HCl and MeOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known by persons skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable higher molecular weight oligo- or polyethylene glycol is used instead of triethylene glycol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 10 synthesis of 2-(2-(2-(allyloxy)ethoxy)ethoxy)ethyl 16-mercapto-6-oxohexadecanoate and analogues derived from higher polyethylene glycols.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 6-oxo-15-hexadecenoic acid and 2 molar equivalents of triethylene glycol are dissolved in dry ethyl acetate. The solution is stirred and cooled down to 0°C. 1.2 molar equivalents dicyclohexyl-carbodiimide (DCC) is added and the solution is stirred for 30 min. Next, the solution is stirred for 3 days at room temperature. The product is purified on a silica column using a suitable mixture of organic solvents, known by the person skilled in the art. The resulting product is concentrated using rotary evaporation
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1 is dissolved in ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using a ethyl acetate/methanol (95/5) mixture as an eluent.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2, is dissolved in CH 2 Cl 2 - 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of allyl bromide is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known by the person skilled in the art.
  • a fourth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 3 is dissolved in a solution containing 1 M HCl and MeOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known by persons skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethylene glycol of higher molecular weight is used instead of triethylene glycol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol and 1,5 molar equivalents of sodium hydride are dissolved in 50 mL DMF. The solution is stirred for 30 min. 1,5 molar equivalents of methyl bromo-acetate is added and the solution is stirred for 24 hours under an atmosphere of argon. The product is quenched with 25 mL of methanol. The solution is then extracted with diethyl ether and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1 is dissolved in methanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated under UV light for 24 h under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing methanol/1M NaOH (3/1). The solution is stirred for 24 hours. HCl is added to acidify the solution. The solution is then extracted with CH 2 Cl 2 and H 2 O. The organic phase is dried on MgSO 4 . The product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a fourth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 3 and 1.2 molar equivalent phenol is dissolved in dry ethyl acetate. The solution is stirred and cooled down to 0°C. 1.2 molar equivalents dicyclohexyl-carbodiimide (DCC) is added and the solution is stirred for 30 min. Next, the solution is stirred for 3 days at room temperature. The product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • DCC dicyclohexyl-carbodiimide
  • a fifth step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 4 and 2 molar equivalents HNO 3 in H 2 SO 4 is added. The solution is stirred for 24 hours. The solution is then extracted with organic solvents and H 2 O. The organic phase is dried on MgSO 4 . The product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethyleneglycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 12 synthesis of 2- ⁇ 2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy ⁇ ethoxy propene and analogues derived from higher polyethylene glycols.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol is dissolved in ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(Isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon. The product is purified by filtering on a glassfilter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • AIBN 2,2'-azobis(Isobutyronitrile)
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1, is dissolved in CH 2 Cl 2 . 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of allyl bromide is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and MeOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol is dissolved in ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(Isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 h under an atmosphere of argon. The product is purified by filtering on a glassfilter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • AIBN 2,2'-azobis(Isobutyronitrile)
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1, is dissolved in an organic solvent. 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of sulfuryl chloride fluoride is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known by the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and MeOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or poly-ethyleneglycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 14 synthesis of 2-(2-(2-(11-mercaptoyldisulfanyl-undecyloxy)-ethoxy)ethoxy)ethoxy sulfonylchloride and analogues derived from higher polyethylene glycols.
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol is dissolved in ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated under UV for 24 h under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • a second step in a dry bottle comprising a magnetic stirrer and 1 molar equivalent of the product obtained in step 1 is dissolved in a solution containing methanol / 1M NaOH (3/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is purified on a silica column using a suitable mixture of organic solvents, known the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2, is dissolved in an organic solvent. 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of sulfuryl chloride fluoride is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol is dissolved in Ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 h under an atmosphere of argon. The product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • AIBN 2,2'-azobis(isobutyronitrile)
  • a second step in a dry bottle comprising a magnetic stirrer and 1 molar equivalent of the product obtained in step 1 is dissolved in a solution containing methanol / 1 M NaOH (3/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2, is dissolved in an organic solvent. 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of chloromethyl thiocyanate is then added and the solution is stirred for 24 h under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol is dissolved in Ethanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(Isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon. The product is purified by filtering on a glassfilter followed by rotary evaporation at reduced pressure and by purification on a silica column using an ethyl acetate/methanol (95/5) mixture as an eluent.
  • AIBN 2,2'-azobis(Isobutyronitrile)
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1, is dissolved in CH 2 Cl 2 . 1,5 molar equivalents of triethylamine is added and the solution is stirred for 1 hour under an atmosphere of argon. 1,5 molar equivalents of chloromethyl thiocyanate is then added and the solution is stirred for 24 hours under an atmosphere of argon.
  • the product is purified by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and MeOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 17 synthesis of 2-(2-(2-(2-(11-mercaptoundecyloxy)ethoxy)ethoxy)-ethoxy)methyl 1,3-chloropropanone and analogues derived from higher polyethylene glycols.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol and 1,5 molar equivalents of sodium hydride are dissolved in 50 mL DMF. The solution is stirred for 30 minutes. 1,5 molar equivalents of 3-chloropropionyl chloride is added and the solution is stirred for 24 hours under an atmosphere of argon. The product is quenched with 25 mL of methanol. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1 is dissolved in methanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis (isobutyronitrile) (AIBN) are added and the solution is irradiated under UV light for 24 hours under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and EtOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 18 synthesis of 2-(2-(2-(2-(11-mercaptoundecyloxy)ethoxy)-ethoxy)ethoxy)methyl 4-fluorophenyl and analogues derived from higher polyethylene glycols.
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol and 1,5 molar equivalents of sodium hydride are dissolved in 50 mL DMF. The solution is stirred for 30 minutes. 1,5 molar equivalents of 4-fluorobenzylchloride is added and the solution is stirred for 24 hours under an atmosphere of argon. The product is quenched with 25 mL of methanol. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1 is dissolved in methanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and EtOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 22 synthesis of 2,3,4,5,6-(2-(2-(2-(2-(2-(11-mercaptoundecyloxy)ethoxy)-ethoxy)ethoxy)methyl-pentafluorophenyl and analogues derived from higher polyethylene glycols
  • the present molecule is synthesized according to the following synthesis scheme:
  • a first step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of 2- ⁇ 2-[2-(undec-10-enyloxy)ethoxy]ethoxy ⁇ ethanol and 1,5 molar equivalents of NaH are dissolved in 50 mL DMF. The solution is stirred for 30 minutes. 1,5 molar equivalents of alpha-bromo-2,3,4,5,6-pentafluorotoluene is added and the solution is stirred for 24 hours under an atmosphere of argon. The product is quenched with 25 mL of methanol. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known by persons skilled in the art. The resulting product is concentrated using rotary evaporation.
  • a second step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 1 is dissolved in methanol. 4 molar equivalents of thioacetic acid and 10 mg of 2,2'-azobis(isobutyronitrile) (AIBN) are added and the solution is irradiated for 24 hours under an atmosphere of argon.
  • the product is purified by filtering on a glass filter followed by rotary evaporation at reduced pressure and by purification on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art.
  • a third step in a dry bottle comprising a magnetic stirrer and under argon atmosphere, 1 molar equivalent of the product obtained in step 2 is dissolved in a solution containing 1 M HCl and EtOH (1/1). The solution is stirred for 24 hours. The solution is then extracted with an organic solvent and H 2 O. The organic phase is dried on MgSO 4 . The product is then concentrated using rotary evaporation. Next, the product is purified on a silica column using a suitable mixture of organic solvents, known to the person skilled in the art. The product is again concentrated using rotary evaporation.
  • n taking any value between 3 and 15,000 provided that a suitable oligo- or polyethylene glycol derivative is used instead of 2-12-[2-(undec-10-enyloxy)ethoxy]ethoxylethanol. If necessary, type and/or amount of solvent and/or reaction time may be adapted in view of n, especially accounting for the physical state (liquid or solid) and the solubility of the polyethylene glycol involved.
  • Example 30 method for preparing a device
  • the step of contacting the metal layer with one or more molecules according to the first aspect of the present invention can for instance be performed as follows.
  • the metal substrate such as gold is cleaned using UV/O 3 treatment.
  • the molecules can be deposited from a water-free organic solvent like for example tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the metal substrates are deposited in this (for example 1 mM) solution and the optimal time (at least 3h) is used to organize the thiols into a self-assembled monolayer (SAM). Afterwards the substrate with the SAM is rinsed with THF and dried with nitrogen. Next step is putting this substrate in a solution with the recognition molecules.
  • the recognition molecules will covalently bind without any activation step.
  • Example 31 method for preparing a device
  • the metal substrate such as gold is cleaned using UV/O 3 treatment.
  • the molecules can be deposited from a water-free organic solvent like for example tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the metal substrates are deposited in this (for example 1 mM) solution containing a mixture of molecules according to the first aspect of the present invention and molecules of the formula Y 1 -([CH 2 ] t -CH 2 -O) n -R 3 -S-Y 2 in chosen proportions.
  • the optimal time (at least 3h) is used to organize the thiols into a self-assembled monolayer (SAM). Afterwards the substrate with the SAM is rinsed with THF and dried with nitrogen. Next step is putting this substrate in a solution with the recognition molecules.
  • the recognition molecules will covalently bind without any activation step.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Nanotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Medical Informatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Composite Materials (AREA)
  • Manufacturing & Machinery (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Adhesives Or Adhesive Processes (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Claims (13)

  1. Molekül mit einer Strukturformel X1-(CH2)c-O-([CH2],-CH2-O)n-R1-S-X2, wobei:
    - X2 entweder H oder S-R5 ist,
    - R5 ein organischer Spacer ist, ausgewählt aus der Gruppe, bestchend aus R2-(O-CH2-[CH2]t)n-O-(CH2)c-X1' und R3-(O-CH2-[CH2]t)n-Y1,
    - t 1 oder 2 ist,
    - c ein Ganzzahliges von O bis 3 ist,
    - n ein Ganzzahliges von 3 bis 15000 ist,
    - R1, R2 und R3 jeweils unabhängig voneinander eine gesättigte oder ethylenisch ungesättigte Hydrocarbylgruppe mit 3 bis 30 Kohlenstoffatomen sind, ausgewählt aus der Gruppe, bestehend aus Alkyl, Alkenyl, Cycloalkyl, Cycloalkyl-Alkyl, Cycloalkenyl, Cycloalkenylalkyl und Cycloalkylalkenyl, wobei die Gruppe wahlweise ein oder mehrere Heteroatome umfasst, ausgewählt aus Stickstoff, Sauerstoff und Schwefel in der Hauptkette, und die Gruppe wahlweise ein oder mehrer Oxo-Substituenten aufweist,
    - Y1 entweder Hydroxy oder Methoxy ist,
    - X1 und X1' jeweils unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Fluorophenyl, Fluorobenzoyl, Fluorophenoxycarbonyl, Nitrophenoxycarbonyl, Oxiranyl, Aziridinyl, C2-12-Alkenyl, Imino-Ether, Dichlorotriazinyl, Sulfonylhalogenid, Alkoxycarbonyl, Isothiocyanat, Isocyanat, Carbonylhalogenid, Haloalkylcarbonyl, Carbonsäureanhydrid, Diazoniumcarbonyl, N-(2-Oxotetrahydro-3-thienyl)-Amid und N-Carboxy-thiazolidinyl-2-thion.
  2. Vorrichtung zur Immobilisierung wenigstens eines Biomoleküls durch eine kovalente Bindung, wobei die Vorrichtung umfasst:
    - ein Substrat mit einer Metallschicht,
    - ein oder mehrere erste Species, die auf die Metallschicht gebunden sind, wobei jede der ein oder mehreren ersten Species ein Molekül ist mit einer Strukturformel X1-(CH2)c-O-([CH2]t-CH2-O)n-R1-S-M, wobei
    - M die Metallschicht ist, an die ein oder mehrere Moleküle gebunden sind,
    - t ein Ganzzahliges von 1 bis 2 ist,
    - n ein Ganzzahliges von 3 bis 15000 ist,
    - c ein Ganzzahliges von 0 bis 3 ist,
    - R1 eine gesättigte oder ethylenisch ungesättigte Hydrocarbylgruppe mit 3 bis 30 Kohlenstoffatomen sind, ausgewählt aus der Gruppe, bestehend aus Alkyl, Alkenyl, Cycloalkyl, Cycloalkyl-Alkyl, Cycloalkenyl, Cycloalkenylalkyl und Cycloalkylalkenyl, wobei die Gruppe wahlweise ein oder mehrere Heteroatome umfasst, ausgewählt aus Stickstoff, Sauerstoff und Schwefel in der Hauptkette, und die Gruppe wahlweise ein oder mehrer Oxo-Substituenten aufweist,
    - X1 ausgewählt ist aus der Gruppe, bestehend aus Fluorophenyl, Fluorobenzoyl, Fluorophenoxycarbonyl, Nitrophenoxycarbonyl, Oxiranyl, Aziridinyl, C2-12 Alkenyl, Imino-Ether, Dichlorotriazinyl, Sulfonylhalogenid, Alkoxycarbonyl, Isothiocyanat, Isocyanat, Carbonylhalogenid, Haloalkylcarbonyl, Carbonsäureanhydrid, Diazoniumcarbonyl, N-(2-Oxotetrahydro-3-thienyl)-Amid und N-Carboxy-thiazolidinyl-2-thion.
  3. Vorrichtung nach Anspruch 2, wobei die Metallschicht ein oder mehrere Metalle umfasst aus der Gruppe, bestehend aus Gold, Silber, Quecksilber, Aluminium, Platin, Palladium, Kupfer, Kadmium, Blei, Eisen, Chrom, Mangan, Wolfram und Legierungen hiervon.
  4. Vorrichtung nach Anspruch 2 oder 3, wobei das zumindest eine Biomolekül wenigstens eine primäre Aminogruppe besitzt und durch die Reaktion der primären Aminogruppe mit der ein oder mehreren ersten Species immobilisierbar ist.
  5. Vorrichtung nach einem der Ansprüche 2 bis 4, weiterhin umfassend ein oder mehrere zweite Species, die auf die Metallschicht gebunden sind, wobei jede der ein oder mehreren zweiten Species ein Molekül mit einer Strukturformel Y1-([CH2]tCH2-O)n-R3-S-M ist, wobei:
    R3 eine gesättigte oder ethylenisch ungesättigte Hydrocarbylgruppe mit 3 bis 30 Kohlenstoffatomen ist, ausgewählt aus der Gruppe, bestehend aus Alkyl, Alkenyl, Cycloalkyl, Cycloalkyl-Alkyl, Cycloalkenyl, Cycloalkenylalkyl und Cycloalkylalkenyl, wobei die Gruppe wahlweise ein oder mehrere Heteroatome umfasst, ausgewählt aus Stickstoff, Sauerstoff und Schwefel in der Hauptkette, und die Gruppe wahlweise ein oder mehrer Oxo-Substituenten aufweist,
    - t ein Ganzzahliges von 1 bis 2 ist,
    - n ein Ganzzahliges von 3 bis 15000 ist,
    - M die Metallschicht ist, an die ein oder mehrere Moleküle gebunden sind,
    - Y1, entweder eine Hydroxygruppe oder eine Methoxygruppe ist.
  6. Vorrichtung nach einem der Ansprüche 2 bis 4, wobei die ein oder mehrere erste Species eine Monolage auf der Metallschicht bilden.
  7. Vorrichtung nach Anspruch 5, wobei die eine oder mehrere der ersten Species und die eine oder mehrere der zweiten Species eine Misch-Monolage auf der Metallschicht bilden.
  8. Verfahren zur Herstellung einer Vorrichtung nach Anspruch 2, umfassend die Schritte:
    a) Bereitstellen einer Metallschicht,
    b) In Kontaktbringen der Metallschicht mit ein oder mehreren Molekülen nach Anspruch 1, wobei die ein oder mehreren Moleküle sich selbst miteinander verbinden, um eine Schicht aus ein oder mehreren der ersten Species, gebunden auf der Metallschicht, zu bilden, wobei jede der ein oder mehreren ersten Species ein Molekül mit einer Strukturformel X1-(CH2)c-O-([CH2]t-CH2-O)n-R1-S-M ist, wobei
    - M die Metallschicht ist, an die ein oder mehrere Moleküle gebunden sind,
    - t ein Ganzzahliges von 1 bis 2 ist,
    - n ein Ganzzahliges von 3 bis 15000 ist,
    - c ein Ganzzahliges von 0 bis 3 ist,
    - R1 eine gesättigte oder ethylenisch ungesättigte Hydrocarbylgruppe mit 3 bis 30 Kohlenstoffatomen ist, ausgewählt aus der Gruppe, bestehend aus Alkyl, Alkenyl, Cycloalkyl, Cycloalkyl-Alkyl, Cycloalkenyl, Cycloalkenylalkyl und Cycloalkylalkenyl, wobei die Gruppe wahlweise ein oder mehrere Heteroatome umfasst, ausgewählt aus Stickstoff, Sauerstoff und Schwefel in der Hauptkette, und die Gruppe wahlweise ein oder mehrer Oxo-Substituenten aufweist,
    - X1 ausgewählt ist aus der Gruppe, bestehend aus Fluorophenyl, Fluorobenzoyl, Fluorophenoxycarbonyl, Nitrophenoxycarbonyl, Oxiranyl, Aziridinyl, C2-12 Alkenyl, Imino-Ether, Dichlorotriazinyl, Sulfonylhalogenid, Alkoxycarbonyl, Isothiocyanat, Isocyanat, Carbonylhalogenid, Haloalkylcarbonyl, Carbonsäureanhydrid, Diazoniumcarbonyl, N-(2-Oxotetrahydro-3-thienyl)-Amid und N-Carboxy-thiazolidinyl-2-thion.
  9. Verfahren zur Herstellung einer Vorrichtung nach Anspruch 5, umfassend die Schritte:
    a) Bereitstellen einer Metallschicht,
    b) In Kontaktbringen der Metallschicht mit ein oder mehreren Molekülen nach Anspruch 1 und mit ein oder mehreren Molekülen mit der Formel Y1-([CH2]t-CH2-O)n-R3-S-Y2,
    wobei die ein oder mehreren Moleküle nach Anspruch 1 und die ein oder mehreren Moleküle mit der Formel Y1-([CH2]tCH2-O)n-R3-S-Y2 sich selbst verbinden, um eine Misch-Lage der ein oder mehreren der ersten Species und der ein oder mehreren der zweiten Species, gebunden auf die Metallschicht, zu bilden, wobei jede der ein oder mehreren ersten Species ein Molekül mit einer Strukturformel X1-(CH2)c-O-([CH2],-CH2-O)n-R1-S-M ist und jede der ein oder mehreren der zweiten Species ein Molekül Y1-([CH2]t-CH2-O)n-R3-S-M ist, wobei:
    - Y2 entweder H oder -S-R4-(O-CH2-[CH2]t)n-Y1' ist,
    - R1, R3 und R4 jeweils unabhängig voneinander eine gesättigte oder ethylenisch ungesättigte Hydrocarbylgruppe mit 3 bis 30 Kohlenstoffatomen sind, ausgewählt aus der Gruppe, bestehend aus Alkyl, Alkenyl, Cycloalkyl, Cycloalkyl-Alkyl, Cycloalkenyl, Cycloalkenylalkyl und Cycloalkylalkenyl, wobei die Gruppe wahlweise ein oder mehrere Heteroatome umfasst, ausgewählt aus Stickstoff, Sauerstoff und Schwefel in der Hauptkette, und die Gruppe wahlweise ein oder mehrer Oxo-Substituenten aufweist,
    - Y1 und Y1' unabhängig voneinander entweder eine Hydroxygruppe oder eine Methoxygruppe sind,
    - M die Metallschicht ist, an die ein oder mehrere Moleküle gebunden sind,
    - t ein Ganzzahliges von 1 bis 2 ist,
    - n ein Ganzzahliges von 3 bis 15000 ist,
    - c ein Ganzzahliges von 0 bis 3 ist, und
    - X1 ausgewählt ist aus der Gruppe, bestehend aus Fluorophenyl, Fluorobenzoyl, Fluorophenoxycarbonyl, Nitrophenoxycarbonyl, Oxiranyl, Aziridinyl, C2-12 Alkenyl, Imino-Ether, Dichlorotriazinyl, Sulfonylhalogenid, Alkoxycarbonyl, lsothiocyanat, Isocyanat, Carbonylhalogenid, Haloalkylcarbonyl, Carbonsäureanhydrid, Diazoniumcarbonyl, N-(2-Oxotetrahydro-3-tienyl)-Amid und N-Carboxy-thiazolidinyl-2-thion.
  10. Sensor zum Nachweis eines Analyten in einer Probenflüssigkeit, wobei der Sensor umfasst:
    - eine Vorrichtung nach einem der Ansprüche 2 bis 7, auf der zumindest ein Biomolekül durch eine kovalente Bindung immobilisiert ist, und
    - einen Überträger.
  11. Verfahren zur Herstellung eines Sensors nach Anspruch 10, wobei das Verfahren die Schritte umfasst:
    - In Kontaktbringen einer Vorrichtung nach einem der Ansprüche 2 bis 7 mit einer Lösung aus zumindest einem Biomolekül,
    - in Kontaktbringen der Vorrichtung mit einem Überträger.
  12. Verfahren nach Anspruch 11, wobei zumindest ein Biomolekül zumindest eine primäre Aminogruppe aufweist.
  13. Verfahren nach Anspruch 11 oder Anspruch 12, wobei die Vorrichtung und/oder das zumindest eine Biomolekül vor dem in Kontaktbringen nicht chemisch aktiviert wird.
EP06026155A 2005-12-16 2006-12-18 Zur Bindung an Metallschichten geeignete Moleküle zur kovalenten Immobilisierung von Biomolekülen Active EP1798250B1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US75138305P 2005-12-16 2005-12-16

Publications (3)

Publication Number Publication Date
EP1798250A2 EP1798250A2 (de) 2007-06-20
EP1798250A3 EP1798250A3 (de) 2007-07-04
EP1798250B1 true EP1798250B1 (de) 2008-09-03

Family

ID=38024430

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06026155A Active EP1798250B1 (de) 2005-12-16 2006-12-18 Zur Bindung an Metallschichten geeignete Moleküle zur kovalenten Immobilisierung von Biomolekülen

Country Status (4)

Country Link
US (2) US7770437B2 (de)
EP (1) EP1798250B1 (de)
AT (1) ATE407163T1 (de)
DE (1) DE602006002585D1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532189A (zh) * 2012-01-12 2012-07-04 西北师范大学 一种超分子金属凝胶的制备

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090030257A1 (en) * 2007-07-25 2009-01-29 Ceramoptec Industries Inc. Anti-microbial photodynamic therapy
JP2008185494A (ja) * 2007-01-31 2008-08-14 Fujifilm Corp 生理活性物質固定化基板
CA2891048A1 (en) 2012-11-19 2014-05-22 Institut Curie Method for grafting polymers on metallic substrates
EP3067439B1 (de) * 2015-03-13 2018-05-09 IMEC vzw Stromlose Metallabscheidung auf einer Mn- oder MnNx-Barriere
US20170059561A1 (en) * 2015-08-28 2017-03-02 The Florida International University Board Of Trustees Thermally Stable Electrochemical Sensor With Long Shelf-Life
US11903328B2 (en) * 2020-02-07 2024-02-13 International Business Machines Corporation Self assembled monolayer formed on a quantum device

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4435454B2 (ja) * 2001-09-03 2010-03-17 富士フイルム株式会社 バイオセンサー用表面
EP1369692A3 (de) * 2002-06-04 2003-12-17 Interuniversitaire Microelectronica Centrum vzw ( IMEC) Sensoroberfläche

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532189A (zh) * 2012-01-12 2012-07-04 西北师范大学 一种超分子金属凝胶的制备
CN102532189B (zh) * 2012-01-12 2014-07-23 西北师范大学 一种超分子金属凝胶的制备

Also Published As

Publication number Publication date
EP1798250A2 (de) 2007-06-20
US20100284860A1 (en) 2010-11-11
US7770437B2 (en) 2010-08-10
DE602006002585D1 (de) 2008-10-16
US8142720B2 (en) 2012-03-27
US20070272003A1 (en) 2007-11-29
EP1798250A3 (de) 2007-07-04
ATE407163T1 (de) 2008-09-15

Similar Documents

Publication Publication Date Title
EP1798250B1 (de) Zur Bindung an Metallschichten geeignete Moleküle zur kovalenten Immobilisierung von Biomolekülen
US8198390B2 (en) Self assembled grafted polymeric layer for use in biosensor technology
US7285674B2 (en) Silane molecules with pre-activated and protein-resistant functionalities and silane films comprising such molecules
JP5588430B2 (ja) 標識独立検出のための表面及びその方法
JP2008545969A (ja) カーボンナノチューブをベースとするグルコースセンサー
JP5027249B2 (ja) アミン捕捉のための表面結合するフッ素化エステル
JP5717138B2 (ja) タンパク質固定化表面修飾材料
Böcking et al. Formation of Tetra (ethylene oxide) Terminated Si− C Linked Monolayers and Their Derivatization with Glycine: An Example of a Generic Strategy for the Immobilization of Biomolecules on Silicon
US6485984B1 (en) Calixcrown derivatives, a process for the preparation thereof, a self-assembled mono-layer of the calixcrown derivatives prepared by using the same and a process for immobilizing a protein mono-layer by using the self-assembled mono-layer of the calixcrown derivatives
Huang Advanced surface modification technologies for biosensors
CA2326043A1 (en) Functionalised silicon surfaces, and method for their production
Yoon et al. Biocatalytic precipitation induced by an affinity reaction on dendrimer-activated surfaces for the electrochemical signaling from immunosensors
Dadfar et al. Evaluation of click chemistry microarrays for immunosensing of alpha-fetoprotein (AFP)
Won et al. Bioelectrocatalytic signaling from immunosensors with back‐filling immobilization of glucose oxidase on biorecognition surfaces
JP4036961B2 (ja) 情報発信型分子認識高分子およびその調製法ならびに使用方法
JP2007057458A (ja) バイオセンサー
Bi et al. Complexation of copper ions with histidine-containing tripeptides immobilized on solid surfaces
JP4911415B2 (ja) 非特異性吸着抑制材料
JP2006143715A (ja) 新規のリンカー化合物、該化合物がコーティングされている基板、該化合物を利用してマイクロアレイを製造する方法、及びそれによって製造されたマイクロアレイ
KR101317321B1 (ko) 혈청 아밀로이드 ｐ 요소 단백질의 분자각인 칩
US20040018532A1 (en) Electronic sensor device
JP2006327984A (ja) ヘテロ二官能性オリゴエチレングリコールの合成方法及びこれを用いたバイオセンサーの製造方法
JP7312403B2 (ja) 新規化合物及びそれを用いたセンサーチップ
Jiménez Meneses Study of substrate modulation and bioreceptor anchoring for the development of high performance microarrays
EP1369692A2 (de) Sensoroberfläche

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

RIC1 Information provided on ipc code assigned before grant

Ipc: C08G 65/00 20060101AFI20070418BHEP

Ipc: G01N 33/543 20060101ALI20070529BHEP

17P Request for examination filed

Effective date: 20070727

AKX Designation fees paid

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 602006002585

Country of ref document: DE

Date of ref document: 20081016

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081214

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090103

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090203

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081231

26N No opposition filed

Effective date: 20090604

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090304

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081204

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602006002585

Country of ref document: DE

Owner name: IMEC, BE

Free format text: FORMER OWNER: INTERUNIVERSITAIR MICROELEKTRONICA CENTRUM VZW (IMEC), LEUVEN, BE

Effective date: 20110429

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20101231

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20101231

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230513

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231121

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20231122

Year of fee payment: 18

Ref country code: DE

Payment date: 20231121

Year of fee payment: 18